Kumada-Corriu cross coupling route to the anti-cancer agent combretastatin A-4

Article abstract of DOI:10.1080/00397910802238692

A short and efficient synthesis of the anticancer agent combretastatin A-4 was accomplished from inexpensive starting materials using the iron-catalyzed cross-coupling of a Grignard reagent and a bromostilbene as the key step. Copyright Taylor & Francis Group, LLC.

Full text of DOI:10.1080/00397910802238692

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Kumada–Corriu Cross Coupling
Route to the Anti-Cancer Agent
Combretastatin A-4
a
Alejandro A. Camacho-Dávila
a
Facultad de Ciencias Químicas, Universidad
Autónoma de Chihuahua , Chihuahua, México
Published online: 14 Oct 2008.
To cite this article: Alejandro A. Camacho-Dávila (2008) Kumada–Corriu
Cross Coupling Route to the Anti-Cancer Agent Combretastatin A-4, Synthetic
Communications: An International Journal for Rapid Communication of Synthetic
Organic Chemistry, 38:21, 3823-3833, DOI: 10.1080/00397910802238692
To link to this article: http://dx.doi.org/10.1080/00397910802238692
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1
Synthetic Communications , 38: 3823–3833, 2008
Copyright # Taylor & Francis Group, LLC
ISSN: 0039-7911 print=1532-2432 online
DOI: 10.1080/00397910802238692
Kumada–Corriu Cross Coupling Route to the
Anti-Cancer Agent Combretastatin A-4
Alejandro A. Camacho-D ꢀa vila
Facultad de Ciencias Qu ´ı micas, Universidad Aut oꢀ noma de Chihuahua,
Chihuahua, M e´ xico
Abstract: A short and efficient synthesis of the anticancer agent combretastatin
A-4 was accomplished from inexpensive starting materials using the iron-
catalyzed cross-coupling of a Grignard reagent and a bromostilbene as the key step.
Keywords: Anticancer, cross-coupling, iron catalysis, stilbene
Combretastatin A-4 (CA-4) (Figure 1) 1 is the most active member of a
group of naturally occurring stilbenes isolated from the african shrub
[1]
Combretum caffrum by Pettit et al. Despite its simple structure, CA-4
has showed marked biological activity and interacts strongly with the col-
chicine site on tubulin. Pronounced cytotoxic activity against several can-
cer cell lines such L1210 lymphocytic leukaemia cells and the P388
[
2]
murine leukemia cell line in the mM range has been demonstrated. Vas-
culature inhibition of solid tumors by CA-4 has also been demon-
[
3]
strated.
Structure–activity studies have shown that the E isomer of 1 and ana-
logs show a much lower activity, therefore to access the biologically
[
4]
active Z isomers stereoselective synthetic routes are required. Also,
the presence of the 3,4,5-trimethoxybenzene substitution in ring A is cru-
cial to biological activity. Studies have also shown that ring B can be
[
5]
modified to a larger extent to yield potent analogs. Some of these are
presented in Fig. 2. The water-soluble phosphate 4 is actually under
Received January 15, 2008.
Address correspondence to Alejandro A. Camacho-D ꢀa vila, Apartado Postal
1
542-C, Chihuahua, Chih. 31170, M e´ xico. E-mail: acamach@uach.mx
3
823

3824
A. A. Camacho-D ꢀa vila
Figure 1. Structure of combretastatin A-4.
[
6]
clinical trials as vascular tumor targeting agent. All of these properties
coupled with its simple structure have encouraged the synthetic efforts
[
7]
toward CA-4 and its analogs, and several syntheses have been reported.
[
1,8]
Synthetic routes based on the Wittig reaction,
[10]
Perkin condensa-
[3,11]
[
tion, Suzuki cross coupling,
9]
Sonogashira cross-coupling,
have all been reported. Some of these
and
[12]
Ramber–Backlund reaction
reactions suffer either from poor stereocontrol of the double-bond
geometry or low yield and are therefore difficult to carry out on a
preparative scale.
A very useful reaction for the stereoselective synthesis of Z or E stil-
benes is the Kumada–Corriu cross-coupling reaction, which involves the
coupling of aryl or vinylmagnesium organometallics A and vinyl or aryl
halides B by the use of catalysts derived from palladium, nickel, or iron to
Figure 2. Structure of combretastatin A-4 analogs.

Synthesis of Combretastatin A-4
3825
Scheme 1.
obtain cross-coupling products of type C in good yields with retention of
the double-bond configuration (Scheme 1).
[13,14]
Previous reports on the
Kumada–Corriu cross-coupling between the aryl and vinyl compounds
shows that this reaction take place more effectively when the organome-
[
14a]
tallic part is on the aryl side rather than on the vinyl side.
The biological importance of combretastatins and specifically of
CA-4 1 prompted us to explore a practical synthesis of 1 using a metal-
catalyzed cross-coupling between Z vinyl bromide 6 and arylmagnesium
bromide 7 (Scheme 2). There are no previous reports on the synthesis
of combretastatin A-4 or its analogs using the Kumada–Corriu cross-
coupling, although this reaction has been used on several occasions
in the synthesis of other stilbenes, mainly through the use of palladium
[
15]
catalysts.
The synthesis of combretastatin A-4 therefore started with the synth-
esis of 5-bromo-2-methoxyphenol 10 prepared via treatment of the inex-
pensive guaiacol 9 with acetic anhydride and triethylamine, followed by
bromination of the resulting acetate. Saponification using potassium
[
16]
hydroxide in methanol afforded 10 in 78% yield over three steps.
The phenolic function was then protected in almost quantitative yield
as the TBDMS ether 11 by reaction of 10 with tert-butyldimethylchloro-
[
silane and imidazole in DMF as solvent (Scheme 3).
17]
Scheme 2.

3826
A. A. Camacho-D ꢀa vila
Scheme 3.
Next, the synthesis of Z-bromostyrene 6 was investigated. Stereoi-
somerically pure 3,4,5-trimethoxy-(Z)-b-bromostyrene 6 has been pre-
viously obtained stereoselectively by the Corey–Fuchs reaction between
aldehyde 12 and carbon tetrabromide to afford 3,4,5-trimethoxydibro-
mostyrene 13. Palladium-catalyzed reduction of 13 with tributyltin
hydride provided (Z)-bromide 6 in 76% yield as the exclusive isomer
[
18]
(Scheme 4).
The main drawback of this procedure that precludes its use in a prac-
tical synthesis of 1 is the use of highly toxic tin compounds and the poor
atom economy. The problems associated with this method prompted us
Scheme 4.

Synthesis of Combretastatin A-4
3827
Scheme 5.
to explore an alternate route to this compound. To this end, the dehydro-
halodecarboxylation of dibromocinnamic acids, a reaction that provides
[
19]
Z-bromostyrenes stereoselectively and in good yield, was explored.
Base-induced dehydrobromodecarboxylation of 3,4,5-trimethoxydibro-
mocinnamic (obtained by bromination of the commercially available
3
,4,5-trimethoxycinnamic acid 14) was accomplished with triethylamine
[19]
in DMF according to the reported procedure to afford bromostyrene
in 89% yield (Scheme 5). The proton NMR of the product showed it to
6
be an inseparable mixture of E and Z isomers in a ratio of 82:18. This
result agrees with the previously reported procedure where the debromo-
decarboxylation of 15 was carried out with triethylamine using micro-
[
20]
waves.
The cause for this reduction on the Z-isomer formation
selectivity may derive from the presence of the electron-donating groups
on the aromatic ring causing a reduction on the stereospecificity of the
bromine addition. It is well known that during the addition of bromine
to electron-rich aromatic systems, the stabilization of the positive charge
is more important than the formation of a cyclic bromonium ion. This
result in a reduction on the erythro=threo stereoselectivity of the dibromo
addition product, which is reflected on the dehalodecarboxylation
[
21]
product.
Although this sequence affords a mixture of isomers, the predomi-
nance of the required Z isomer and the use of inexpensive starting mate-
rials allows for the large-scale preparation of 1 if coupling of vinyl
bromide 6 with the protected Grignard reagent 7 proceeds stereoselec-
tively and in high yield. To this end, the metal-catalyzed cross-coupling
reaction using the mixture of isomers of 6 and Grignard reagent 7 was
examined.
Cahiez and Knochel have reported the iron(III)-catalyzed cross-
coupling reaction between arylmagnesium halides and alkenyl halides
using the inexpensive ferric acetylacetonate as catalyst. This reaction
afforded the corresponding coupling products with retention of stereo-
[22]
chemistry of the double bond.
It was very pleasing to find that the

3828
A. A. Camacho-D ꢀa vila
coupling of protected Grignard reagent 7 (1.25 equivalents) and vinyl
ꢀ
bromide 6 in the presence of 5 mol% of iron(III) acetylacetonate at 0 C
in THF proceeded in a favorable way. Column chromatography of the
reaction product afforded in elution order the dimethoxybiphenyl TBS
ether resulting from the homo coupling of Grignard reagent 7 in 10–
1
8
2% yield, followed by pure Z combretastatin A-4 TBDMS ether isomer
in 61% yield, then a mixture of Z=E isomers of TBDMS ether of com-
bretastatin, and finally, some unreacted vinyl halide (the Z=E isomer
ratio of this product was not analyzed). Increasing the catalyst load to
10 mol% did not improve the yield of cross-coupling product but caused
an increase in the Grignard homocoupling product (25–30%). Finally,
deprotection of pure Z-combretatstatin A-4 TBDMS ether 8 was accom-
plished by treatment with KF-2H O in methanol at room temperature
2
for 2 h to provide pure Z-combretastatin A-4 1 in 95% yield after chro-
matographic workup.
In summary, the iron(III)-catalyzed Kumada–Corriu cross-coupling
reaction has been utilized in a efficient way to reach the biologically
active stilbene combretastatin A-4 from inexpensive starting materials
in a 40% overall yield. This route can also be applied to the synthesis
of other more potent analogs of 1.
EXPERIMENTAL
THF was distilled from sodium-benzophenone under argon atmosphere.
Thin-layer chromatography (TLC) was performed on SiO plates. SiO
2
2
(70–230 mesh) was used for column chromatography. NMR was
obtained with a Varian Gemini XL200 or Varian Unity at 400 MHz with
CHCl signal as internal reference. All coupling reactions were done
3
under argon using flame-dried glassware.
cis þ trans-3,4,5-Trimethoxybromostyrene (6)
To a stirred solution of 3,4,5-trimethoxycinnamic acid (8.8 g, 37 mmol) in
chloroform (55 mL), a solution of bromine (6.24 g, 39 mmol) in chloro-
form (10 mL) was added dropwise at room temperature. After the addi-
tion, the reaction mixture was stirred 1 h more and then the chloroform
was removed in vacuo to afford the dibromo acid as a solid residue.
The crude dibromoacid was dissolved in DMF (50 mL) and cooled at
ꢀ
0
C in an ice-water bath. Then Et N (11.53 g, 114 mmol) was added drop-
3
wise. The reaction mixture was stirred while reaching room temperature,
and the stirring continued for 8 h. The reaction mixture was partitioned

Synthesis of Combretastatin A-4
3829
between water and chloroform (100 mL). The layers were separated,
and the aqueous phase extracted with chloroform. The combined
organic extracts were washed successively with water (4 ꢁ 100 mL),
3
N HCl (100 mL), and saturated NaHCO solution and dried over
3
Na SO . Solvent removal in vacuo afforded a brown oil, which was
2
4
purified by column chromatography (SiO ) eluting with hexane=
2
EtOAc (9=1) to afford 8.99 g (89%) of a 82:18 mixture of cis- and
1
trans-3,4,5-trimethoxybromostyrene as an oil. H NMR d: 3.83–3.90
(
E and Z-OCH3 9.1 H), 6.37 (0.80 H, d, J ¼ 8.4 Hz, Z), 6.51 (0.35
H, s, E), 6.68 (0.27H, d, J ¼ 13.92 Hz, E), 6.95–7.05 (2.63 H, m).
5
-Bromo-2-methoxyphenol (10)
NBS (9.43 g, 53 mmol) was added to a solution of guaiacol acetate (8 g,
48 mmol) in acetonitrile (120 mL), and the reaction mixture was heated
ꢀ
at 60 C during 12 h. The reaction mixture was diluted with EtOAc
(
150 mL) and quenched with water (150 mL). The layers were separated,
and the aqueous phase was extracted with EtOAc (3 ꢁ 50 mL). The com-
bined organic extracts were washed with aqueous sodium sulfite solution,
water, and brine. Solvent removal afforded a viscous oil, which was dis-
solved in methanol, and then a solution of KOH (5.6 g, 100 mmol) in
methanol was added. The mixture was refluxed under argon for 5 h
and then acidified with 6 N HCl (50 mL). The reaction was extracted with
CH Cl (100 mL), and the aqueous layer was extracted again with
2
2
CH Cl . The combined organic extracts were washed with water and
2
2
brine and dried (Na SO ). Solvent removal and chromatography of the
2
4
residue (SiO ) eluting with hexane=EtOAc (8=2) afforded bromophenol
2
ꢀ
0 as crystals (8.0 g, 82%), mp 101–103 C. H NMR d: CDCl : 3.76
3
1
1
(
s 3H), 6.58 (d, 1H), 6.83–6.89 (d, 1H), 6.97 (d, 1H).
5
-Bromo-2-methoxyphenol t-Butyldimethylsilyl Ether (11)
t-Butyldimethylchlorosilane (5 g, 33.17 mmol) was added to a stirred
solution of 5-bromo-2-methoxyphenol (6.66 g, 32.8 mmol) and imidazole
(
4.53 g, 66 mmol) in DMF (20 mL). The reaction mixture was stirred 16 h
at room temperature, and then the mixture was partitioned between hex-
anes and water. After separation of the phases, the organic layer was
washed with water and dried (Na SO ). Solvent removal in vacuo
2
4
afforded TBS ether 11 as an oil (9.95 g, 96%). This was pure enough to
be used without further purification.

3830
A. A. Camacho-D ꢀa vila
1
H NMR d: CDCl : 0.15 (s, 6H), 0.99 (s, 9H), 3.78 (s, 3H), 6.69 (1H,
3
d, J ¼ 8.4 Hz), 6.99 (d, 1H, J ¼ 1.7 Hz), 7.20 (1H, dd, J ¼ 8.4 and 1.7 Hz).
tert-Butyldimethylsilyl Ether of Combretastatin A-4 (8)
ꢀ
To an ice-cooled (ꢂ5 to 0 C) solution of the mixture of bromostyrenes 6
(
(
2.73 g, 10 mmol) and 265 mg (5 mol%) of [Fe(acac) ] in a mixture of THF
3
20 mL), and NMP (2 mL), a solution of the Grignard 7 reagent prepared
from 4.75 g (15 mmol, 1.5 equiv) of 5-bromo-2-methoxyphenol t-butyldi-
methylsilyl ether 11 and magnesium (600 mg) in THF (25 mL) was added
dropwise via syringe. After the addition, stirring continued for 30 min,
and then the reaction mixture was quenched by addition of saturated
NH Cl solution (50 mL). The phases were separated, and the aqueous
4
layer was extracted with Et O. The combined organic phases were
2
washed with brine and dried (Na SO ). Solvents were removed in vacuo,
2
4
and the residue was purified by column chromatography (SiO ) to afford
2
1
2
.63 g (61% yield) of CA-4 TBS ether 8 as an oil. H NMR d: CDCl :
3
6
.71–6.88 (m, 3H), 6.50 (s, 2H), 6.45 (d, 2H, J ¼ 12), 3.83 (s 3H), 3.78
(s, 3H), 3.70 (s, 6H), 0.93 (s, 9H), 0.05 (s, 6H).
C NMR d: CDCl : 153.1, 150.5, 144.8, 133.3, 130.25, 129.9, 128.9,
1
3
3
123.1, 121.5, 111.85, 106.07, 61.1, 56.1, 55.7, 25.9, 18.6, ꢂ4.55. IR (NaCl
neat): 3000, 2955, 2933, 2858, 2838, 1580, 1511, 1505, 1464, 1455, 1424,
1
391, 1361, 1327, 1281, 1236, 1184, 1156, 1129, 1032, 1110, 995, 963,
ꢂ1
813, 784 cm . The spectral data for this compound were identical to
those reported.
[10]
Combretastatin A-4 (1)
Potassium fluoride dihydrate (1 g) was added to a solution of the silyl
ether 8 (1 g, 2.32 mmol) in methanol (10 L). The mixture was stirred under
argon. TLC monitoring of the reaction showed the disappearance of
starting material after 40 min. After this time, the mixture was diluted
with dichloromethane (10 mL) and quenched with water (10 mL). The
phases were separated, and the aqueous layer was extracted with dichlor-
omethane in three portions. The combined organic extracts were washed
with water and dried (Na SO ). Solvent removal and chromatography of
2
4
the residue on SiO (hexane=EtOAc 4:1 ! 2:1) afforded a viscous oil that
2
1
slowly solidified on standing (0.797 g, 92% yield). H NMR d: CDCl :
3
6
6
3
.92 (d, 1H, J ¼ 1.82), 6.80 (1H, dd, J ¼ 2, 8.4), 6.73 (d, 1H, J ¼ 8.4),
.52 (s, 2H), 6.44 (d, 2H, J ¼ 12), 5.51 (s, 1H, br), 3.87 (s, 3H), 3.84 (s,
H), 3.70 (s, 6H).13C NMR d: CDCl : 153.07, 146.02, 145.45, 137.34,
3

Synthesis of Combretastatin A-4
3831
1
5
1
32.93, 130.81, 129.71, 129.22, 121.32, 115.27, 110.56, 106.28, 61.15,
6.15. IR (neat) NaCl: 3426, 3004, 2938, 2837, 1614, 1579, 1508, 1462,
456, 1419, 1328, 1274, 1237, 1182, 1127, 1027, 1005, 881, 855, 794,
ꢂ1
7
reported.
61 cm . The spectral data of this compound were identical to those
[
10]
ACKNOWLEDGMENT
Support by James W. Herndon, Department of Chemistry and Biochem-
istry, New Mexico State University, USA, is gratefully acknowledged.
REFERENCES
1
2
3
4
5
. Pettit, G. R.; Singh, S. B.; Boyd, M. R.; Hamel, E.; Pettit, R. K.; Schmidt, J.
M.; Hogan, F. Isolation and synthesis of combretastatins A-4, A-5, and A-6.
J. Med. Chem. 1995, 38, 1666–1672.
. Bohle, A. S.; Leuschner, I.; Kalthoff, H.; Henne-Bruns, D. Combretastatin
A-4 prodrug: A potent inhibitor of malignant hemangioendothelioma cell
proliferation. Int. J. Cancer 2000, 87, 838–843.
. Tozer, G. M.; Kanthou, C.; Parkins, C. S.; Hill, S. A. The biology of the com-
bretastatins as tumour vascular targeting agents. Int. J. Exp. Pathol. 2002, 83,
21–38.
. Tron, G. C.; Pirali, T.; Sorba, G.; Pagliai, F.; Busacca, S.; Genazzani, A. A.
Medicinal chemistry of combretastatin A4: Present and future directions.
J. Med. Chem. 2006, 49, 3033–3044.
. Gaukroger, K.; Hadfield, J. A.; Lawrence, N. J.; Nolan, S.; McGown, A. T.
Structural requirements for the interaction of combretastatins with tubulin:
How important is the trimethoxy unit? Org. Biomol. Chem. 2003, 1, 3033–
3037.
6
. (a) Pettit, G. R.; Rhodes, M. R. Antineoplastic agents 389: New syntheses
of the combretastatin A-4 prodrug. Anti-Cancer Drug. Design 1998, 13,
183–191; (b) Galbraith, S. M.; Maxwell, R. J.; Lodge, M. A.; Tozer, G.
M.; Wilson, J.; Taylor, N. J.; Stirling, J.; Sena, L.; Padhani, A. R.; Rustin,
G. J. S. Combretastatin A4 phosphate has tumor antivascular activity in
rat and man as demonstrated by dynamic magnetic resonance imaging.
J. Clin. Oncol. 2003, 21, 2831–2842.
7
. For reviews: (a) Brown, T.; Holt, H.; Lee, M. Synthesis of biologically active
heterocyclic stilbene and chalcone analogs of combretastatin. Top. Hetero-
cycl. Chem. 2006, 2, 1–51; (b) Hsieh, H. P.; Liuou, J. P.; Mahindroo, N. Phar-
maceutical design of antimitotic agents based on combretastatins. Curr.
Pharm. Design 2005, 11, 1665–1677; (c) Dzierzbicka, K.; Kolodziejczyk, A.
M. Combretastatin A-4 and its analogues as antineoplastic agents. Polish
J. Chem. 2004, 78, 323–342; (d) Cirla, A.; Mann, J. Combretastatins: From

3832
A. A. Camacho-D ꢀa vila
natural products to drug discovery. Nat. Prod. Rep. 2003, 20, 558–564; (e)
Nam, N.-H. Combretastatin A-4 analogues as antimitotic antitumor agents.
Curr. Med. Chem. 2003, 10, 1697–1722.
8. Lawrence, N. J.; Muhammad, F. The synthesis of alkenes via epi-
phosphonium species, 1: An anti-Wittig elimination. Tetrahedron 1998, 54,
15345–15360.
9
. Gaukroger, K.; Hadfield, J. A.; Hepworth, L. A.; Lawrence, N. J.; McGown,
A. T. Novel syntheses of cis and trans isomers of combretastatin A-4. J. Org.
Chem. 2001, 66, 8135–8138.
1
1
1
1
0. F u¨ rstner, A.; Nikolakis, K. Ethynylation of aryl halides by a modified Suzuki
reaction: Application to the syntheses of combretastatin A-4, A-5 and lunu-
laric acid. Liebigs Ann. 1996, 2107–2113.
1. Lawrence, N. J.; Ghani, F. A.; Hepworth, L. A.; Hadfield, J. A.; McGown,
A. T.; Pritchard, R. G. The synthesis of (E) and (Z)-combretastatins A-4 and
a phenanthrene from Combretum caffrum. Synthesis 1999, 1656–1660.
2. Robinson, J. E.; Taylor, R. J. K. A Ramberg–B a¨ cklund route to the stilbe-
noid anti-cancer agents combretastatin A-4 and DMU-212. Chem. Commun.
2007, 1617–1619.
3. Reviews: (a) Kumada, N. Nickel and palladium complex catalyzed cross-
coupling reactions of organometallic reagents with organic halides. Pure
Appl. Chem. 1980, 52, 669–679; (b) Huo, S.; Negishi, E.-I. In Handbook of
Organopalladium Chemistry for Organic Synthesis, E.-I. Negishi (Ed.); Wiley:
New York, 2002; vol. 1, pp. 335–408; (c) Takahashi, T.; Kano, K. In Modern
Organonickel Chemistry, Y. Tamaru (Ed.); Wiley-VCH: Weinheim, 2005;
pp. 41–55.
1
4. (a) Tamao, K.; Sumitani, K.; Kiso, Y.; Zembayashi, M.; Fujioka, A.;
Kodama, S.-I.; Nakajima, I.; Minato, A.; Kumada, M. Nickel-phosphine
complex-catalyzed Grignard coupling. I. Cross-coupling of alkyl, aryl, and
alkenyl Grignard reagents with aryl and alkenyl halides: General scope and
limitations. Bull. Soc. Chem. Jpn. 1976, 49, 1958–1969; (b) Lebedev, S. A.;
Sorokina, R. S.; Petrov, E. S. Synthesis of styrenes by cross-coupling substi-
tuted phenylmagnesium bromides with vinyl bromide in the presence of a
nickel complex. Russ. J. Org. Chem. 1989, 25, 2026–2027; (c) Molander, G.
A.; Rahn, B. J.; Shubert, D. C.; Bonde, S. E. Iron catalyzed cross-coupling
reactions: Synthesis of arylethenes. Tetrahedron Lett. 1983, 24, 5449–5452.
5. For a review of the synthesis of stilbenes: Ferr e´ : Filmon, K.; Delaude, L.;
Demonceau, A.; Noels, A. F. Catalytic methods for the synthesis of stilbenes with
an emphasis on their phytoalexins. Coord. Chem. Rev. 2004, 248, 2323–2336.
6. Paraskar, A. S.; Sudalai, A. Co-catalyzed reductive cyclization of azido and
1
1
cyano substituted a,b-unsaturated esters with NaBH : Enantioselective synth-
4
esis of (R)-baclofen and (R)-rolipram. Tetrahedron 2006, 62, 4907–4916.
7. Ramacciotti, A.; Fiaschi, R.; Napolitano, E. Enantioselective synthesis of
natural combretastatin. Tetrahedron: Asymmetry 1996, 7, 1101–1104.
8. Herz, H.-G.; Queiroz, M. J. R. P.; Maas, G. 2-Arylvinylation of 1-methylin-
dole by palladium-catalyzed cross-coupling reactions. Synthesis 1999,
1
1
1013–1016.

Synthesis of Combretastatin A-4
3833
1
2
2
9. Kim, S. H.; Wei, H.-X.; Willis, S.; Li, G. A mild procedure for the stereospe-
cific transformation of trans cinnamic acid derivatives to cis b-bromostyrenes.
Synth. Commun. 1999, 29, 4179–4185.
0. Kuang, C.; Yang, Q.; Senboku, H.; Tokuda, M. Synthesis of (Z)-1-bromo-
1-alkenes and terminal alkynes from anti-2,3-dibromoalkanoic acids by
microwave-induced reaction. Tetrahedron 2005, 61, 4043–4052.
1. (a) Ruasse, M. F.; Argile, A.; Dubois, J. E. Reactivity of ethylenic com-
pounds, 42: The multipathway mechanism in styrene bromination: Competi-
tion between bromonium and carbonium ion intermediates. J. Am. Chem.
Soc. 1978, 100, 7645–7652; (b) Fahey, R. C. The stereochemistry of electro-
philic additions to olefins and acetylenes. Top. Stereochem. 1968, 3, 237–342.
2. (a) Cahiez, G.; Avedissian, H. Highly stereo- and chemoselective iron-
catalyzed alkenylation of organomagnesium compounds. Synthesis 1998,
2
1199–1205; (b) Dohle, W.; Kopp, F.; Cahiez, G.; Knochel, P. Fe(III)-
catalyzed cross-coupling between functionalized arylmagnesium compounds
and alkenyl halides. Synlett. 2001, 1901–1904.